5-Alkyl-1,6-naphthyridin-2(1H)-ones and cardiotonic use thereof

ABSTRACT

1-R&#34;-3-Q-4-R&#39;-5-R-1,6-naphthyridin-2(1H)-ones (I) or salts thereof, where R is lower-alkyl, R&#39; is hydrogen or methyl, R&#34; is hydrogen or lower-alkyl, and Q is hydrogen, hydroxy, amino, cyano, carbamyl, carboxy or aminocarbamyl, are useful as cardiotonic agents (I, Q is hydrogen, hydroxy, amino, cyano or carbamyl) and/or intermediates therefor (I, Q is carboxy, aminocarbamyl, hydrogen, amino, cyano or carbamyl). Also shown are 3-Q&#39;-4-R&#39;-5-(RCO)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinones (II) or salts thereof, where R and R&#39; are as above and Q&#39; is hydrogen or cyano, which are useful as cardiotonics (II, Q&#39; is hydrogen) and/or intermediates (II, Q&#39; is cyano or hydrogen). Processes for preparing the compounds of formulas I and II are shown.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending application Ser.No. 404,454, filed Aug. 2, 1982 and now U.S. Pat. No. 4,415,580, issuedNov. 15, 1983.

Lesher and Singh copending U.S. patent application Ser. No. 357,872,filed Mar. 15, 1982, now U.S. Pat. No. 4,412,077 discloses and claimscompounds used herein as intermediates, namely, 3-Q-4-R₂-5-(lower-alkanoyl)-6-methyl-2(1H)-pyridinones, cardiotonic agents,where Q is hydrogen or cyano and R₂ is hydrogen or methyl.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 5-(lower-alkyl)-1,6-naphthyridin-2(1H)-ones,their cardiotonic use and their preparation.

(b) Information Disclosure Statement

Chemical Abstracts 72, 12,615d (1970) is reproduced as follows:"Chemotherapeutics. IV. 1,6-Naphthyridine N-oxides. Takahashi Torizo;Hamada Yoshiki; Takeuchi Isao; Uchiyama Hideko (Fac. Pharm., MeijoUniv., Nagoya, Japan). Yakugaku Zasshi 1969, 89(9), 1260-5 (Japan).Various reaction conditions were examd. for the formulation of I, II,III, and IV by the application of hydrogen peroxide to 1,6-naphthyridinein HOAc soln. ##STR1## Ir, uv, NMR, and mass spectra of these fourcompds. were measured to detect their structure, which was detd. bychem. methods such as redn. with Raney Ni. Antibacterial action of I,II, and III was examd."

2-Hydroxy-3-methyl-1,6-naphthyridine, the tautomeric form of3-methyl-1,6-naphthyridin-2(1H)-one, was reportedly prepared by Ogata etal. [Chem Pharm Bull. 20, 2264 (1972)] in two steps by firstphotocylization of N-(4-pyridinyl)methacrylamide to produce1,2,3,4-tetrahydro-3-methyl-2-oxo-1,6-naphthyridine and thendehydrogenating said tetrahydro compound by heating it in acetic acid.

3-Cyano-2-hydroxy-1,6-naphthyridine, the tautomeric form of3-cyano-1,6-naphthyridin-2(1H)-one, was reportedly prepared by Hawes etal [J. Med. Chem. 16, 849 (1973)] by refluxing 4-aminonicotinaldehydeand ethyl cyanoacetate in ethanol in the presence of piperidine. Thecompound was reportedly used as an intermediate for preparing2-amino-3-cyano-1,6-naphthyridine, a "potential diuretic agent", and isshown as having low diuretic activity.

In another paper Hawes et al [J. Heterocycl. Chem. 11, 151 (1974)] showthe preparations of: (a) 3-cyano-1,6-naphthyridin-2(1H)-one by reacting4-aminonicotinaldehyde with N,N-dimethylcyanoacetamide or4-cyanoacetylmorpholine in the presence of piperidine; (b)3-carbamyl-1,6-naphthyridin-2(1H)-one by using malonamide in place ofN,N-dimethylcyanoacetamide as in (a); and, (c)3-carbethoxy-1,6-naphthyridin-2(1H)-one by using diethyl malonateinstead of malonamide as in (b).

Moller et al [Ann. 612, 153 (1957)] show as intermediates the3-R-4-OH-1,6-naphthyridines where R is H, NH₂ and COOH.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention resides in5-(lower-alkyl)-3-Q-1,6-naphthyridin-2(1H)-ones or salts thereof, whichare useful as cardiotonic agents and/or intermediates, where Q ishydrogen, hydroxy, amino, cyano, carbamyl, carboxy or aminocarbamyl.

In a composition aspect, the invention resides in a cardiotoniccomposition for increasing cardiac contractility which comprises apharmaceutically acceptable carrier and, as the active componentthereof, a cardiotonically effective amount of5-(lower-alkyl)-3-Q-1,6-naphthyridin-2(1H)-one or salt thereof, where Qis hydrogen, hydroxy, amino, cyano or carbamyl.

In a method aspect, the invention resides in a method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering to such patient a cardiotonically effectiveamount of 5-(lower-alkyl)-3-Q-1,6-naphthyridin-2(1H)-one or saltthereof, where Q is hydrogen, hydroxy, amino, cyano or carbamyl or1,6-naphthyridin-2(1H)-one or salt thereof.

The invention in its process aspects comprises: (a) reacting a5-(lower-alkanoyl)-3-Q'-6-methyl-2(1H)-pyridinone withdi-(lower-alkyl)formamide di-(lower-alkyl) acetal to produce5-(lower-alkanoyl)-3-Q'-6-[2-(di-loweralkylamino)ethenyl]-2(1H)-pyridinone(II), where Q' is cyano or hydrogen; (b) reacting II with formamidine orammonia or salt thereof to produce3-Q'-5-(lower-alkyl)-1,6-naphthyridin-2(1H)-one, where Q' is cyano orhydrogen; (c) converting3-cyano-5-(lower-alkyl)-1,6-naphthyridin-2(1H)-one successively to thecorresponding 3-carboxy and 3-unsubstituted compounds; (d) converting3-cyano-5-(lower-alkyl)-1,6-naphthyridin-2(1H)-one to the corresponding3-carbamyl and 3-aminocarbamyl compounds; (e) converting 3-carbamyl(oraminocarbamyl)-5-(lower-alkyl)-1,6-naphthyridin-2(1H)-one to thecorresponding 3-amino- 5-(lower-alkyl)-1,6-naphthyridin-2(1H)-one; and,(f) converting said 3-amino compound to the corresponding 3-hydroxycompound.

Another aspect of the invention resides in1,2-dihydro-5,6-dimethyl-2-oxo-1,6-naphthyridinium4-methylbenzenesulfonate, useful as a cardiotonic agent.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

In a composition of matter aspect the invention resides in1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-one having the formula I##STR2## or acid-addition or cationic salt thereof, where R islower-alkyl, R' is hydrogen or methyl, R" is hydrogen or lower-alkyl,and Q is hydrogen, hydroxy, amino, cyano, carbamyl, carboxy oraminocarbamyl. The compounds of formula I where Q is hydrogen, hydroxy,amino, cyano or carbamyl are useful as cardiotonic agents, as determinedby standard pharmacological evaluation procedures. Preferred embodimentsare those of formula I where R is methyl, ethyl or propyl, R' and R" areeach hydrogen, and Q is hydrogen, hydroxy, amino or cyano. Particularlypreferred embodiments are those of formula I where R is methyl, ethyl orpropyl, R' and R" are each hydrogen, and Q is hydrogen. The compounds offormula I where Q is carboxy or aminocarbamyl as well as the compoundswhere Q is hydrogen, amino, cyano or carbamyl are useful asintermediates as shown hereinbelow.

A composition aspect of the invention resides in the cardiotoniccomposition for increasing cardiac contractility which comprises apharmaceutically acceptable carrier and, as the active componentthereof, a cardiotonically effective amount of1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-one having the formula I orpharmaceutically acceptable acid-addition or cationic salt thereof,where R, R' and R" have the meanings given for formula I and Q ishydrogen, hydroxy, amino, cyano or carbamyl. Preferred embodiments ofthis aspect of the invention are the compositions having as the activecomponent said compound where R is methyl, ethyl or propyl, R' and R"are each hydrogen, and Q is hydrogen, hydroxy, amino or cyano.Particularily preferred embodiments are those compositions having asactive component the compound of formula I where R is methyl, ethyl orpropyl, R' and R" are each hydrogen, and Q is hydrogen.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient a cardiotonically effective amount of1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-one having the formula I orpharmaceutically acceptable acid-addition or cationic salt thereof,where R, R' and R" have the meanings given for formula I, Q is hydrogen,hydroxy, amino, cyano or carbamyl, and also where R is hydrogen when Qis hydrogen. Preferred embodiments are the methods using said compoundof formula I where R is methyl, ethyl or propyl, R' and R" are eachhydrogen, and Q is hydrogen, hydroxy, amino or cyano. Particularlypreferred embodiments are those methods using as active component thecompound of formula I where R is methyl, ethyl or propyl, R' and R" areeach hydrogen, and Q is hydrogen.

A process aspect of the invention resides in the process which comprisesreacting 3-Q'-4-R'-5-(RCO)-6-methyl-2(1H)-pyridinone withdi-(lower-alkyl)formamide di-(lower-alkyl) acetal to produce3-Q'-4-R'-5-(RCO)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinonehaving formula II ##STR3## where Q' is hydrogen or cyano, R' is hydrogenor methyl, and R, R₁ and R₂ are each lower-alkyl. The compounds offormula II where Q' is cyano as well as those where Q' is hydrogen areuseful as intermediates for preparing said above compounds havingformula I where Q is cyano or hydrogen respectively.

Another process aspect of the invention resides in the process whichcomprises reacting3-Q'-4-R'-5-(RCO)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinone offormula II with formamidine or ammonia or salt thereof to produce3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-one having formula I where Q and Q',are each cyano or hydrogen, R' is hydrogen or methyl, R is lower-alkyland R" is hydrogen. The reaction is run preferably using ammoniumacetate.

Another process aspect of the invention resides in the process whichcomprises successively converting3-cyano-4-R'-5-R-1,6-naphthyridin-2(1H)-one, where R' is hydrogen ormethyl and R is lower-alkyl, to the corresponding 3-carboxy and3-unsubstituted compounds by respectively hydrolyzing the 3-cyanocompound to produce the 3-carboxy compound and decarboxylating the3-carboxy compound.

Another process aspect of the invention resides in the process whichcomprises successively converting3-cyano-4-R'-5-R-1,6-naphthyridin-2(1H)-one, where R' is hydrogen ormethyl and R is lower-alkyl, to the corresponding 3-carbamyl and3-aminocarbamyl compounds by respectively hydrolyzing the 3-cyanocompound to produce the 3-carbamyl compound and reacting the 3-carbamylcompound with hydrazine to produce the 3-aminocarbamyl compound.

Another process aspect of the invention resides in the process whichcomprises converting 3-carbamyl or3-aminocarbamyl-4-R'-5-R-1,6-naphthyridin-2(1H)-one to the corresponding3-amino-4-R'-5-R-1,6-naphthyridin-2(1H)-one, where R' is hydrogen ormethyl and R is lower-alkyl, respectively, by reacting the 3-carbamylcompound with a reagent capable of converting carbamyl to amino or byreacting the 3-aminocarbamyl compound with a reagent capable ofconverting carboxylic acid hydrazide to amino.

Another process aspect of the invention resides in the process whichcomprises converting 3-amino-4-R'-5-R-1,6-naphthyridin-2(1H)-one to thecorresponding 3-hydroxy-4-R'-5-R-1,6-naphthyridin-2(1H)-one, where R' ishydrogen or methyl and R is lower-alkyl, by heating the 3-amino compoundwith aqueous alkali solution.

Another aspect of the invention resides in1,2-dihydro-5,6-dimethyl-2-oxo-1,6-naphthyridinium4-methyl-benzenesulfonate, which is useful as a cardiotonic agent.

The term "lower-alkyl" as used herein, e.g., as the meaning of R informula I or II or of R₁ or R₂ in formula II or as one of the meaningsof R" in formula I means alkyl radicals having from 1 to 4 carbon atomswhich can be arranged as straight or branched chains, illustrated bymethyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl andisobutyl.

The compound of formula I is useful both in the free base form and inthe form of acid-addition salts, and, both forms are within the purviewof the invention. The acid-addition salts are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the base form. The acids which can be used to prepare theacid-addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are relatively innocuous to the animal organism inpharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base are not vitiated by side effectsascribable to the anions. Appropriate pharmaceutically acceptable saltswithin the scope of the invention are those derived from mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid and sulfamic acid; and organic acid such as lactic acid, aceticacid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamicacid, quinic acid, and the like, giving the hydrochloride, hydrobromide,sulfate, phosphate, sulfamate, lactate, acetate, citrate, tartrate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compound of formula I are preparedeither by dissolving the free base in aqueous or aqueous-alcoholsolution or other suitable solvents containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and acid in an organic solvent, in which case the salt separatesdirectly or can be obtained by concentration of the solution. Theacid-addition salts of said basic compound of formula II are similarlyprepared but under anhydrous conditions.

Although pharmaceutically acceptable salts of said basic compound offormula I are preferred, all acid-addition salts are within the scope ofthe invention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically acceptable salt by ionexchange procedures.

Other pharmaceutically acceptable salts of said compound of formula Iare those cationic salts derived from strong inorganic or organic bases,e.g., sodium hydroxide, potassium hydroxide, trimethylammoniumhydroxide, to produce the corresponding cationic salt, e.g., sodium,potassium, trimethylammonium salt, respectively.

The molecular structures of the compounds of formulas I and II wereassigned on the basis of evidence provided by infrared, ultraviolet,nuclear magnetic resonance and mass spectra, by the correspondence ofcalculated and found values for the elemental analyses, and, by theirmethod of preparation.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows.

The reaction of 3-Q'-4-R'-5-(RCO)-6-methyl-2(1H)-pyridinone withdi-(lower-alkyl)formamide di-(lower-alkyl) acetal to produce3-Q'-4-R'-5-(RCO)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinone(II) is carried out by mixing the reactants at about 35° to 100° C.

The preparation of the intermediate3-Q'-4-R'-5-(RCO)-6-methyl-2(1H)-pyridinones, which are disclosed andclaimed in said copending application Ser. No. 357,872, filed Mar. 15,1982, are described in the following five paragraphs.

The preparation of 3-Q'-5-(RCO)-6-methyl-2(1H)-pyridinone or3-Q'-5-(RCO)-4,6-dimethyl-2(1H)-pyridinone, where Q' is hydrogen and Ris lower-alkyl is carried out by heating at about 100° C. to 150° C.2-(RCO)-1-methyl-ethenamine with a lower-alkyl, perferably methyl orethyl, 2-propynoate or 2-butynoate, respectively, with or without asuitable solvent.

The intermediate 2-(RCO)-1-methyl-ethenamines are generally knowncompounds which are prepared by conventional means, as illustratedhereinbelow in the specific exemplary disclosure.

The 4-R'-5-(RCO)-6-methyl-1,2-dihydro-2-oxonicotinonitriles or4-R'-5-(RCO)-6-methyl-1,2-dihydro-2-oxonicotinamides are prepared by agenerally known method [Sunthankar et al., Indian J. of Chemistry 11,1315-16 (1973))] or an improved modification thereof, as illustratedhereinbelow in the specific exemplary disclosure.

The 4-R'-5-(RCO)-6-methyl-1,2-dihydro-2-oxonicotinonitriles orcorresponding 4-R'-5-(RCO)-6-methyl-1,2-dihydro-2-oxonicotinamides areconveniently hydrolyzed to produce the correspondingly substitutednicotinic acids under aqueous acidic conditions by heating with aqueousmineral acid, preferably sulfuric acid and preferably at about 70° C. to130° C. Alternatively, this hydrolysis can be carried out under aqueousalkaline conditions, preferably using aqueous sodium or potassiumhydroxide at about 95°-100° C.

Decarboxylation of the 4-R'-5-(RCO)-6-methyl-1,2-dihydro-2-oxonicotinicacids to produce the corresponding4-R'-5-(RCO)-6-methyl-2(1H)-pyridinones is carried out by heating in theabsence or presence of a suitable inert solvent at about 240° C. to 280°C., preferably at about 245° C. to 250° C.

The reaction of II with a formamidine or ammonium salt, preferablyacetate, to produce I where Q is hydrogen or cyano, R' is hydrogen ormethyl, R" is hydrogen and R is lower-alkyl is carried out by heatingthe reactants at about 90° C. to 150° C., preferably about 100° C. to130° C., in a suitable solvent, preferably dimethylformamide, othersolvents being acetic acid, n-butanol, para-dioxane, dimethyl sulfoxide,and the like. Preferred salts of formamidine and ammonia are those ofweak organic or inorganic acids, for example, acetate, citrate, lactate,tartrate, carbonate, and the like, although salts of strong acids, e.g.,hydrochloride and sulfate, also can be used. Optionally and lesspreferably, the reaction can be run using ammonia under pressure.

The partial hydrolysis of I where Q is cyano to produce I where Q iscarbamyl is carried out preferably using concentrated sulfuric acid atabout room temperature, i.e., about 20° C. to 30° C. Optionally, otherstrong inorganic acids, e.g., phosphoric acid, polyphosphoric acid, canbe used in place of sulfuric acid.

The hydrolysis of I where Q is cyano to produce I where Q is carboxy isconveniently carried out by heating the cyano compound with aqueousinorganic acid, preferably sulfuric acid, preferably on a steam bath.Optionally, aqueous phosphoric, hydrochloric, hydrobromic or other acidscan be used.

Decarboxylation of I where Q is carboxy to produce I where Q is hydrogenis carried out by heating the carboxy compound at about 250° to 280° C.in a suitable inert solvent, for example, eutectic mixture of diphenyland diphenyl ether (DOWTHERM® A), mineral oil, and the like.Alternatively, I where Q is cyano can be conveniently converted to Iwhere Q is hydrogen in boiling 85% sulfuric acid.

The conversion of I where Q is carbamyl by reaction with hydrazine toproduce I where Q is aminocarbamyl is conveniently carried out byheating the carbamyl compound preferably with hydrazine hydrate andneutralizing the reaction mixture with acid, e.g., acetic acid.

The conversion of I where Q is aminocarbamyl to produce I where Q isamino is carried out by reacting the aminocarbamyl compound with areagent capable of converting carboxylic acid hydrazide to amino. Thisreaction is run by first reacting the aminocarbamyl compound withnitrous acid in aqueous medium at a low temperature, preferably below 5°C., to form the corresponding compound I where Q is carboxylic acidazide in situ and then stirring the reaction mixture at about 25° to 30°C. until evolution of nitrogen ceases.

The conversion of I where Q is carbamyl to produce I where Q is amino iscarried out by reacting the carbamyl compound with a reagent capable ofconverting carbamyl to amino. The reaction is conveniently run byheating an aqueous mixture containing I where Q is carbamyl and analkali metal hypohalite, preferably hypobromite or hypochlorite, andthen acidifying the reation mixture, preferably with an aqueous mineralacid, e.g., hydrochloric acid. The reaction can be run initially in anice bath and then at room temperature up to about 100° C.

The conversion of I where Q is amino to produce I where Q is hydroxy iscarried out by heating the amino compound at about 80° C. to 100° C.,preferably about 90° C. to 100° C., preferably with aqueous alkalisolution, e.g., 5-30% aqueous sodium or potassium hydroxide, and thenacidifying the reaction mixture

The conversion of 4-R'-5-R-1,6-naphthyridin-2(1H)-one (I, Q is H and R"is H) to 1-CH₃ -4-R'-5-R-1,6-naphthyridin-2(1H)-one (I, Q is H and R" isCH₃) by methylation is conveniently carried out by usingdimethylformamide dimethyl acetal at about 80° C. to 120° C., preferablyabout 90° C. to 110° C. and using an aprotic solvent, e.g.,dimethylformamide. Other solvents include p-dioxane. Alkylation toproduce corresponding 1-R" compounds where R" has from one to fourcarbon atoms can be run by comparably heating the corresponding1-unsubstituted compound with a lower-alkyl ester of a strong inorganicor organic sulfonic acid in a suitable solvent, e.g., dimethylformamide,in the presence of an acid-acceptor, e.g., anhydrous potassiumcarbonate.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 5-(RCO)-6-METHYL-1,2-DIHYDRO-2-OXONICOTINONITRILES

A-1. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile--A solutioncontaining 60 g of dimethylformamide dimethyl acetal and 50 g of2,4-pentanedione was heated on a steam bath for 2.5 hours and cooled. Tothe resulting solution containing3-dimethylaminomethylene-2,4-pentanedione was added 300 ml of methanol,27 g of sodium methoxide and 47 g of cyanoacetamide. The resultingmixture was heated on a steam bath for 4 hours, the hot solution pouredinto 700 ml of water, and the aqueous mixture acidified with acetic acidand chilled in an ice bath. The solid that separated was collected,dried, and heated with 400 ml. of methanol Insoluble material wasfiltered from the hot methanol mixture and the filtrate cooled. Theproduct that separated was collected and dried at 90° C. to produce 24.6g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p. 227°-230°C. [Sunthankar et al., supra, m.p. 231° C.]

A-2. 1,2-Dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile--A mixture containing34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml ofdimethylformamide dimethyl acetal was allowed to stand at roomtemperature overnight and then concentrated on a rotary evaporator atsteam bath temperature to yield, as a liquid,3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g ofcyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirringfor 3 hours and then concentrated in vacuo to remove the methanol. Theresidue was dissolved in 300 ml of warm water and filtered. The filtratewas acidified with acetic acid and the resulting precipitate wascollected, washed with water, dried in vacuo at 90°-95° C. andrecrystallized from dimethylformamide (75 ml) to yield 7.8 g of1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p.265°-268° C. with decomposition. The mother liquor was concentrated todryness and digested with hot methanol and cooled. The separated solidwas dried, 20.2 g, and recrystallized from dimethylformamide to yield9.8 g of finely crystalline material, m.p. 259°-263° C. withdecomposition. The NMR spectral data for this compound indicated it tobe mostly said1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resultingmother liquors were combined and concentrated on a rotary evaporator andthe resulting residue was recrystallized from ethanol to yield 20.4 g ofsolid, m.p. 220°-226° C. The NMR spectral data for this solid indicatedit to be a 5:4 mixture of said1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attemptsto separate the two compounds by fractional crystallization wereunsuccessful; however, the two compounds should be separable.

A-3. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile and5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide--A mixture containing200 g of 2,4-pentanedione and 300 ml of dimethylformamide dimethylacetal was heated under reflux on a steam bath for 5 hours and thenallowed to stand at room temperature overnight. The excess solvent wasdistilled off using a rotary evaporator to a constant weight of 307 g,as an oil, of 3-dimethylaminomethylene-2,4-pentanedione which wascombined with 700 ml of methanol and 168 g of cyanoacetamide followed by108 g of sodium methoxide with stirring and cooling. The reactionmixture was heated under reflux for 7 hours, cooled and treated with 150ml of glacial acetic acid. The separated solid was collected and thefiltrate evaporated to dryness. The residue was treated with 700 ml ofwater and the insoluble material was collected, washed with water anddried. The two solids were combined and refluxed with 1 liter ofmethanol. The insoluble beige solid was collected, washed with hotmethanol and dried in vacuo at 90°-95° C. to yield 55.8 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide, m.p. >320° C. Bothfiltrates were concentrated to a volume of about 800 ml and cooled. Theseparated solid was collected and dried in vacuo at 90°- 95° C. to yield100 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p.226°-229° C. Further concentration of the mother liquors yielded another44.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p.221°-225° C.

A-4. 5-Acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinonitrile--It iscontemplated that this compound can be obtained following the proceduredescribed in Example A-1 using in place of dimethylformamide dimethylacetal a molar equivalent quantity of dimethylacetamide dimethyl acetal.

B. 5-(RCO)-6-METHYL-1,2-DIHYDRO-2-OXONICOTINIC ACID

B-1. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinic Acid--A mixturecontaining 34 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide, 50ml of concentrated sulfuric acid and 100 ml of water was heated on asteam bath with stirring for 6 hours. The hot reaction solution wasfiltered and to the filtrate was added 50 ml of water. The resultingmixture was allowed to stand at room temperature overnight whereupon theproduct crystallized out. The separated product was collected, washedwith water, dried in a vacuum oven at 90°-95° C. to yield 16.8 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 238°-241° C.This acid was recrystallized from methanol and dried to yield 14.7 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 241°-243° C.

B-2. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinic Acid--A mixturecontaining 52.8 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile,150 ml of water and 75 ml of concentrated sulfuric acid was heated on asteam bath for 15 hours whereupon no reaction took place. The reactionmixture was then heated in a oil bath at 130°-140° C. for six hoursallowing the water to evaporate using an air-cooled condenser. Thereaction mixture was allowed to stand at room temperature overnightwhereupon a white crystalline solid separated. The solid was collected,washed with water and dried in a vacuum oven at 90°-95° C. to yield 49 gof 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 239°-241° C.To the filtrate was added aqueous ammonia until the pH was about 4 andthe solid that separated was collected, washed with water and dried invacuo at 90°-95° C. to yield another 5.8 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 238°-241° C.

B-3. 5-Acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinic Acid--It iscontemplated that this compound can be obtained following the proceduredescribed in Example B-2 but using in place of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile a molar equivalentquantity of 5-acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinonitrile.

C. 5-(RCO)-6-METHYL-2(1H)-PYRIDINONES

C-1. 5-Acetyl-6-methyl-2(1H)-pyridinone--A 10 g portion of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid was heated neat in abath of a boiling mixture of diphenyl and diphenyl ether for 40 minutesand the mixture allowed to cool to room temperature. The reactionmixture was dissolved in hot isopropyl alcohol, treated withdecolorizing charcoal and filtered, and the filtrate allowed to stand atroom temperature for several hours. The separated product was collectedand dried at 90°-95° C. to yield 4.3 g of5-acetyl-6-methyl-2-(1H)-pyridinone, m.p. 193°-195° C.

C-2. 5-Acetyl-4,6-dimethyl-2(1H)-pyridinone--It is contemplated thatthis compound can be obtained following the procedure described inExample C-1 using in place of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid a molar equivalentquantity of 5-acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinic acid.

C-3. 5-Acetyl-6-methyl-2(1H)-pyridinone--A mixture containing 100 g of2,4-pentanedione, 200 ml of ethanol and 60 ml of a concentrated aqueousammonium hydroxide was allowed to stand at room temperature over theweekend (3 days) and then concentrated on a rotary evaporator to yield83 g of 4-amino-3-penten-2-one as an oil. To the stirred oil was added70 ml of methyl 2-propynoate over a 10 minute period and the resultingsolution was stirred at ambient temperature for 30 minutes whereupon avigorous exothermic reaction took place. After the exothermic reactionhad subsided, the reaction mixture was heated on a steam bath for 2.5hours, the reaction mixture was then dissolved in 300 ml of boilingisopropyl alcohol, the solution treated with decolorizing charcoal andfiltered, and the filtrate concentrated on a rotary evaporator to yielda viscous liquid. To the viscous liquid was added 300 ml of ether andthe mixture triturated and allowed to stand at room temperatureovernight. The separated solid was collected, washed with ether anddried to yield 84.6 g of material whose nmr spectrum indicated it to bethe uncyclized intermediate, methyl 4-acetyl-5-amino-2,4-hexadienoate.[In another run this compound was isolated, recrystallized from methanoland found to melt at 104°-106° C.] The mother liquor from the above wasconcentrated on a rotary evaporator to a constant weight of 45.6 g ofdark oil. The oil was combined with the uncyclized material anddissolved in 250 ml of dimethylformamide and the resulting mixture wasrefluxed for 4.5 hours. The reaction mixture was allowed to stand atroom temperature overnight whereupon the crystalline product separated.The crystalline precipitate was collected, washed with isopropylalcohol, dried in a vacuum oven at 90°-95° C. to yield 62.5 g of5-acetyl-6-methyl-2(1H)-pyridinone, m.p. 196°-198° C. The mother liquorfrom the above was concentrated to dryness on a rotary evaporator andthe residue dissolved in 100 ml of isopropyl alcohol, the alcoholsolution treated with decolorizing charcoal and filtered and thefiltrate allowed to stand at room temperature overnight. The precipitatethat separated was collected to yield another 15.2 g of5-acetyl-6-methyl-2(1H)-pyridinone, m.p. 194°-196° C.

C-4. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone--A mixture containing 25g of 2,4-hexanedione, 100 ml of ethanol and 25 ml of concentratedaqueous ammonium hydroxide was allowed to stand room temperatureovernight and then concentrated on a rotary evaporator to give 21 g, asa pale yellow oil, a mixture containing 4-amino-3-hexen-2-one and5-amino-4-hexen-3-one. To the oil was added 18.5 g of methyl2-propynoate and the mixture heated in a oil bath at about 100°whereupon a vigorous exothermic reaction took place. After the reactionhad subsided, the reaction mixture was heated in an oil bath at160°-170° C. for 2 hours and then concentrated on a rotary evaporator togive a gummy material. The latter was crystallized from isopropylalcohol-ether to yield 64 g of6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C., whosestructure was confirmed by its NMR spectrum. No other product wasisolated from the mother liquor of the above reaction mixture; however,in another run, Example D-4 hereinbelow, a second product, namely6-ethyl-5-acetyl-2(1H)-pyridinone was isolated.

C-5. 5-Acetyl-4,6-dimethyl-2(1H)-pyridinone--A mixture containing 40 gof 2,4-pentanedione, 100 ml of ethanol and 50 ml of concentrated aqueousammonium hyroxide was allowed to stand at room temperature for 6 hoursand then concentrated on a rotary evaporator to yield, as an oil, 35.4 gof 4-amino-3-penten-2-one. The oil was dissolved in 100 ml ofdimethylformamide and to the solution was added 32 g of methyl2-butynoate and the resulting reaction mixture was refluxed for 95 hoursand then concentrated on a rotary evaporator. The remaining oil residuewas heated with 100 ml of ether whereupon a white solid crystallizedspontaneously. The solid was collected, washed with ether and dried in avacuum oven at 90°-95° C. to yield 25.7 g of5-acetyl-4,6-dimethyl-2(1H)-pyridinone, m p. 160°-162° C.

C-6. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone (and5-Acetyl-6-ethyl-2(1H)-pyridinone)--A mixture containing 50 g of2,4-hexanedione, 100 ml of ethanol and 50 ml of concentrated aqueousammonium hydroxide was allowed to stand at room temperature overnightand then concentrated on a rotary evaporator at 50°-60° C. to a constantweight of 48.8 g, a pale yellow oil that solidified on standing at roomtemperature. The nmr spectrum of this solid in CDCl₃ indicated it to bea mixture of 5-amino-4-hexen-3-one and 4-amino-3-hexen-2-one in a weightratio of 65:35. The mixture of amino-hexen-ones was dissolved in 100 mlof dimethylformamide and treated with methyl 2-propynoate and theresulting mixture was first gently heated with stirring on a steam bathfor 2 hours and then refluxed for 24 hours. The reaction mixture wasallowed to cool to room temperature and allowed to stand at roomtemperature overnight. The crystalline material that separated wascollected, washed with isopropyl alcohol and dried in vacuo at 90°-95°C. to yield 11.9 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p.173°-175° C. The mother liquor was concentrated on a rotary evaporatorand the residue was crystallized from isopropyl alcohol, washed withether and dried to yield another 10.4 g of6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C. (Thefiltrate was concentrated in vacuo to yield 57.8 g of an oily residuewhich was chromatographed on silica gel (700 g) using ether as eluant.Evaporation of the ether fractions yielded 22.4 g of the least polarcomponent, an oily material, a middle fraction of 16.4 g, a viscuousgummy oil, and as the most polar component, 7.8 g, a solid which wasrecrystallized from isopropyl alcohol to yield a white amorphous powder,m.p. 140°-145° C., whose nmr spectrum showed it to consist of 90%5-acetyl-6-ethyl-2(1H)-pyridinone. Six further recrystallizations ofthis product resulted in 1.5 g of pure5-acetyl-6-ethyl-2(1H)-pyridinone, m.p. 162°-164° C., as shown by itsnmr spectrum.)

C-7. 5-(n-Butanoyl)-6-methyl-2(1H)-pyridinone--A mixture containing 22.2g of 3-methyl-5-n-propylisoxazole [Kashima et al., Bull. Chem. Soc.Japan 46, 310-313 (1973)], 500 mg of platinum dioxide and 200 ml ofethanol was hydrogenated under catalytic hydrogenation conditions forninety minutes, the catalyst was filtered off and the filtrate wasconcentrated on a rotary evaporator to yield 18.5 g of colorless residuewhich solidified on cooling. The residue containing2-amino-2-hepten-4-one was dissolved in 50 ml of dimethylformamide andto the solution was added 14.8 g of methyl 2-propynoate. The resultingreaction solution was allowed to stand at ambient temperature for thirtyminutes (exothermic) and then refluxed for three and one half hours. Thedimethylformamide was removed on a rotary evaporator. The remaining darkbrown liquid was heated in an oil bath at 195°-200° C. for four hours,cooled to room temperature, crystallized from isopropyl alcohol anddried at 80°-85° C. to produce, as pale yellow flakes, 9.4 g of5-(n-butanoyl)-6-methyl-2(1H)-pyridinone, m.p. 167°-168° C.

Following the procedure described in Example C-7 using in place of3-methyl-5-n-propylisoxazole a molar equivalent quantity of theappropriate 3-methyl-5-R-isoxazole, it is contemplated that the5-(RCO)-6-methyl-2(1H)-pyridinones of Examples C-8 and C-9 can beprepared via the appropriate 2-amino-2-alken-4-one.

C-8. 6-Methyl-5-(n-pentanoyl)-2(1H)-pyridinone, first using5-n-butyl-3-methylisoxazole and then 2-amino-2-octen 4-one.

C-9. 6-Methyl-5-(3-methylpropanoyl)-2(1H)-pyridinone, first using5-isopropyl-3-methylisoxazole and then 2-amino-5-methyl-2-hexen-4-one.

D.3-Q'-4-R'-5-(RCO)-6-[2-(DI-LOWER-ALKYLAMINO)ETHENYL]-2(1H)-PYRIDINONES

D-1. 5-Acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone--A mixturecontaining 15.1 g of 5-acetyl-6-methyl-2(1H)-pyridinone, 200 ml ofdimethylformamide and 15 ml of dimethylformamide dimethyl acetal wasstirred at room temperature for 30 minutes, heated gently with stirringon a steam bath for 2 hours, then allowed to cool and stirred at roomtemperature overnight. The golden yellow needles that separated werecollected, washed with methanol and dried in a vacuum oven at 80° C. toyield 10.7 g of 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone,m.p. 238°-240° C.

Acid-addition salts of5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone are convenientlyprepared by adding to a mixture of 2 g of5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone in about 40 ml ofmethanol the appropriate acid, e.g., methanesulfonic acid, concentratedsulphuric acid, concentrated phosphoric acid, to a pH of about 2 to 3,chilling the mixture after a partial evaporation and collecting theprecipitated salt, e.g., dimethanesulfonate, sulfate, phosphate,respectively.

D-2. 6-(2-Dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone--Amixture containing 25 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone,200 ml of dimethylformamide and 25 ml of dimethylformamide dimethylacetal was heated on a steam bath for 5 and 1/2 hours and thedimethylformamide was removed by heating the reaction mixture on arotary evaporator. The residue was refluxed with 100 ml of ethanol, themixture cooled, and the yellow solid was collected, washed with ethanoland dried in an oven at 90°-95° C. to yield 12.8 g of6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone, m.p.204°-206° C.

Acid-addition salts of6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone are preparedfollowing the procedure described in Example D-1.

D-3.5-Acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile--Amixture containing 35.2 g of5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 300 ml ofmethanol and 30 ml of dimethylformamide dimethyl acetal was heated withstirring on a steam bath for 4 and 1/2 hours and then allowed to cool toroom temperature. The precipitated yellow solid was collected, washedwith methanol and dried in an oven under reduced pressure at 95° C. toyield 16.4 g of5-acetyl-1,2-dihyro-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile,m.p. 267°-270° C.

Acid-addition salts of5-acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrilecan be prepared following the procedure described in Example D-1.

D-4.1,2-Dihydro-6-(2-dimethylaminoethenyl)-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile--Amixture containing 9.5 g of1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile, 50 mlof dimethylformamide and 8 ml of dimethylformamide dimethyl acetal wasstirred at room temperature overnight and then concentrated to drynesson a rotary evaporator. The residue was refluxed with isopropyl alcohol;the insoluble yellow solid was collected, washed with isopropyl alcoholand dried at 90° C. to yield 2.8 g of1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile,m.p. 278°-280° C. with decomposition. The mother liquor was treated withdecolorizing charcoal, filtered and concentrated to about 150 ml andallowed to stand at room temperature. The product that separated wascollected, washed with isopropyl alcohol and dried to yield another 1.8g of product, m.p. 270° C.

Acid-addition salts of1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrilecan be prepared following the procedure described in Example D-1.

D-5. 5-Acetyl-6-(2-diethylaminoethenyl)-2(1H)-pyridinone can be preparedfollowing the procedure described in Example D-2 using in place ofdimethylformamide dimethyl acetal a molar equivalent quantity ofdiethylformamide diethyl acetal.

Following the procedure described in Example D-1 using in place of5-acetyl-6-methyl-2(1H)-pyridinone a molar equivalent quantity of theappropriate 5-(RCO)-methyl-2(1H)-pyridinone, it is contemplated that thecompounds of Examples D-6, D-7 and D-8 can be prepared.

D-6. 5-(n-Butanoyl)-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone, m.p.203°-205° C. with decomposition, using5-(n-butanoyl)-6-methyl-2(1H)-pyridinone.

D-7. 6-(2-Dimethylaminoethenyl)-5-(n-pentanoyl)-2(1H)-pyridinone, using6-methyl-5-(n-pentanoyl)-2(1H)-pyridinone.

D-8.6-(2-Dimethylaminoethenyl)-5-(3-methyl-n-propanoyl)-2(1H)-pyridinone,using 6-methyl-5-(3-methyl-n-propanoyl)-2(1H)-pyridinone. E.1-R"-3-Q-4-R'-5-R-1,6-NAPHTHYRIDIN-2(1H)-ONES

E-1. 1,2-Dihydro-5-methvl-2-oxo-1,6-naphthyridine-3-carbonitrile--Amixture containing 33.2 g of5-acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridincarbonitrile,32.1 g of formamidine acetate and 300 ml of dimethylformamide was heatedin a oil bath at 120°-130° C. for 3 hours, the original yellow soliddissolving and dark solution resulting. The reaction mixture wasevaporated to dryness and then treated with 400 ml of water followed by30 ml of acetic acid. The resulting insoluble solid was collected,washed with water, air-dried, recrystallized from dimethylformamide anddried at 90° C. to yield 27.4 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile as acompound containing 1/2 mole of dimethylformamide, m.p. 278°-280° C.with decomposition.

The above preparation was also carried out using ammonium acetate inplace of formamidine acetate as follows: A mixture containing 1.305 kgof 1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile,9 liters of dimethylformamide and 915 g of ammonium acetate was refluxedfor five hours The reaction suspension was cooled to 5° C. for threehours and the precipitated product was collected, washed twice with cold60/40 by volume of dimethylformamide/water, twice with cold ethanol,once with ether and dried to yield 826 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile, m.p.75°-277° C.

Acid-addition salts and cationic salts of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile can beprepared following the procedure described in Example E-4.

E-2 1,2-Dihydro-5-methyl-2-oxo-1,6-naphthyridine-3carboxamide--To 200 mlof concentrated sulfuric acid chilled in an ice bath was added withstirring 37 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile and thereaction mixture was allowed to stand at room temperature overnight. Thereaction mixture was then poured on ice (1 liter beaker, half filled),the resulting mixture cooled in an ice bath and then neutralized byadding aqueous ammonium hydroxide, followed by addition of acetic acidto make the mixture slightly acidic. The separated solid was collected,washed with water, air-dried, then recrystallized from a large volume ofdimethylformamide (1.2 1.) and dried at 95° C. to yield 8.4 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide, m.p.>320° C.

Acid-addition salts and cationic salts of this -caraboxamide can beprepared following the procedure described in Example E-4.

E-3. 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acidhydrazide--A mixture containing 34 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide and 150 ml ofhydrazine hydrate was heated on a steam bath for 18 hours and thenstripped to dryness on a steam bath. To the residue was added 100 ml ofwater and the aqueous mixture was neutralized by adding acetic acid. Thefine yellow needles were collected, washed successively with water andmethanol, and then dried at 90° C. to produce 32.6 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acidhydrazide, m.p.>310° C.

E-4. 3-Amino-5-methyl-1,6-naphthyridin-2(1H)-one--To a stirred mixturecontaining 21.8 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazideand 100 ml of concentrated sulphuric acid in 200 ml of water was added asolution containing 8 g of sodium nitrite in 30 ml of water over a 30minute period, maintaining the internal temperature below 5° C. byadding ice to the reaction mixture The mixture was stirred in an icebath for about 2 hours and then at room temperature for about 20 hours.The reaction mixture was concentrated to dryness on a rotary evaporator.The residue was treated with 200 ml of water, neutralized by addingsmall quantities of solid anhydrous potassium carbonate. The resultingyellow solid was collected, washed with water and dried at 90° C. Thefiltrate was evaporated to dryness and then dissolved in a smallquantity of water (about 100 ml) and allowed to stand at roomtemperature over the weekend. The resulting mixture was evaporated todryness on a rotary evaporator; the residue was refluxed with 500 ml ofdimethylformamide; the mixture was filtered; and, the filtrate wasconcentrated to dryness to yield a yellow residue which was swirled with150 ml of water. The solid was collected, washed with water and dried at90° C. to yield 11.2 g of product. This material was recrystallized fromdimethylformamide-ethanol to produce 8.3 g of3-amino-5-methyl-1,6-naphthyridin-2(1H)-one, m.p. 283°-285° C. withdecomposition.

Acid-addition salts of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one areconveniently prepared by adding to a mixture of 1 g of3-amino-5-methyl-1,6-naphthyridin-2(1H)-one in about 20 ml of aqueousmethanol the appro-priate acid, e.g., hydrochloric acid, methanesulfonicacid, concentrated sulfuric acid, concentrated phosphoric acid, to a pHof about 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitated salt, e.g., hydrochloride, methansulfonate,sulfate, phosphate, respectively. Also, the acid-addition salt isconveniently prepared in aqueous solution by adding to water withstirring a molar equivalent quantity each of3-amino-5-methyl-1,6-naphthyridin-2(1H)-one and the appropriate acid,e.g., lactic acid or hydrochloric acid, to prepare respectively thelactate or hydrochloride salt of3-amino-5-methyl-1,6-naphthyridin-2(1H)-one in aqueous solution

Cationic salts of 3-amino-5-methyl-1,6-naphthyridine-2(1H)-one areconveniently prepared by reaction with an equivalent quantity of theappropriate base, for example, sodium hydroxide, potassium hydroxide ortrimethylammonium hydroxide, to produce the corresponding respectivesodium, potassium or trimethylammonium salt.

E-5. 3-Hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one--This compound wasprepared by heating 3-amino-5-methyl-1,6-naphthyridin-2(1H)-onefollowing in part the procedure described in Example E-4 withoutpurification of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one by reactingsaid unpurified 3-amino compound with aqueous sodium hydroxide solutionor by similarly reacting said purified 3-amino compound with aqueoussodium hydroxide solution. These procedures are described as follows.Following the procedure described in Example E-4 using 27 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acidhydrazide, 60 ml of concentrated sulfuric acid, 200 ml of water and 9.1g of sodium nitrite and after concentrating the reaction mixture todryness on a rotary evaporator, the residue containing the correspondingsaid 3-amino compound was treated with 75 ml of 35% sodium hydroxidesolution and 100 ml of water and the resulting aqueous mixture washeated on a steam bath for 30 hours and then acidified with acetic acid.The acidified mixture was allowed to stand at room temperature overnightand the resulting product that separated was collected, washed withwater and air-dried. It was then recrystallized from 400 ml of boilingdimethylformamide, filtering off the insoluble material, concentratingthe filtrate to a volume of about 200 ml and then allowing it to standat room temperature for 3 hours. The yellow crystalline solid wascollected, washed with methanol and dried at 100° C. to yield 7.6 g of3-hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one, m.p.>320° C. The samecompound was also prepared by heating a mixture containing3-amino-5-methyl-1,6-naphthyridin-2(1H)-one with 25 ml of 10% aqueoussodium hydroxide solution on a steam bath for 7 hours and then cooled toroom temperature The reaction mixture was acidified with acetic acid andthe resulting white crystalline precipitate was collected, washed withwater and dried at 95° C. to yield 1.2 g of3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one, m.p.>320° C.

Acid-addition salts and cationic salts of3-hydroxy-5-methyl-1,6-naphthyridine-2(1H)-one can be prepared followingthe procedure described above in Example E-4.

E-6. 1,2-Dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid--Amixture containing 63 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile, 100 ml ofconcentrated sulphuric acid and 100 ml of water was heated on a steambath for 16 hours, after which time tlc analyses (20% methanol in ether)indicated the presence of a considerable amount of starting material.Therefore, the reaction mixture was heated in a oil bath at 135°-140° C.for 8 hours, cooled to room temperature and poured on ice (1 l. beaker,1/3 filled). The resulting aqueous mixture was neutralized by addingaqueous ammonium hydroxide until slightly basic and was then reacidifiedby adding acetic acid. The resulting solid was collected, washedsuccessively with water and methanol, and dried at 100° C. to yield 54.8g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid,m.p. 255°-257° C. with decomposition. Another 7.2 g of the product, m.p.252° -255° C. was obtained from the mother liquor.

E-7a. 5-Methyl-1,6-naphthyridin-2(1H)-one--To 1 l. of boiling eutecticmixture of diphenyl and diphenylether (DOWTHERM® A) was added over a 5minute period 55 g of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid. Thereaction mixture was cooled for 5 minutes and then filtered. Thefiltrate was allowed to stand at room temperature over the weekend. Thecrystalline material that separated from the filtrate was collected,washed with n-hexane and air-dried to give 38.4 g of material, which wasindicated by tlc analysis (20% methanol and ether) to be a mixture. Thismixture was chromatographed using 500 g of silica gel in a 1 l. sinteredglass funnel using 40% to 60% methanol in ether. The less polarcomponent was recrystallized from isopropyl alcohol to produce 22.4 g of5-methyl-1,6-naphthyridin-2(1H)-one, m.p. 235°-237° C.

5-Methyl-1,6-naphthyridin-2(1H)-one also was prepared directly from thecorresponding 3-cyano compound, as follows: A 650 g portion of1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile was addedwith stirring at room temperature to a solution of 2100 ml 8 M sulfuricacid in 350 ml of water. The reaction mixture was stirred mechanicallyand refluxed (internal temperature at 215°-220° C.) for 24 hours. Thedark solution was allowed to come to ambient temperature and poured onice. The solution was stirred and basified with 6 l of concentratedammonium hydroxide to pH 10.5, the internal temperature being maintainedat 20°-30° C. during this addition. The dark beige solid was collectedby filtration, washed with a minimum of cold water and dried in an ovenchamber at 65° overnight. The crude product was recrystallized twicefrom water with decolorizing charcoal treatment to produce 330 g of5-methyl-1,6-naphthyridin-2(1H)-one, m.p. 245°-246° C.

Acid-addition salts of 5-methyl-1,6-naphthyridin-2(1H)-one areconveniently prepared by adding to a mixture of 2 g of5-methyl-1,6-naphthyridin-2(1H)-one in about 40 ml of aqueous methanolthe appropriate acid, e.g., methanesulfonic acid, concentrated sulphuricacid, concentrated phosphoric acid, to a pH of about 2 to 3, chillingthe mixture after partial evaporation and collecting the precipitate,e.g, dimethanesulfonate, sulphate, phosphate, respectively. Also, theacid-addition salt is conveniently prepared in aqueous solution byadding to water with stirring molar equivalent quantities each of5-methyl-1,6-naphthyridin-2-(1H)-one and the appropriate acid, e.g.,lactic acid or hydrochloric acid, to prepare respectively themonolactate or monohydrochloride salt in aqueous solution.

Cationic salts of 5-methyl-1,6-naphthyridin-2(1H)-one are convenientlyprepared by reaction with an equivalent quantity of the appropriatebase, for example, sodium hydroxide, potassium hydroxide ortrimethylammonium hydroxide, to produce the corresponding respectivesodium, potassium or trimethylammonium salt.

E-7b. 5-Methyl-1,6-naphthyridin-2(1H)-one--A mixture containing 10.3 gof 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone, 10.4 g offormamidine acetate and 75 ml of dimethylformamide was heated on a steambath for 5 hours and then concentrated to dryness on a rotaryevaporator. The residue was treated with 50 ml of water and againstripped to dryness The white residue was recrystallized from isopropylalcohol to yield 6.7 g of 5-methyl-1,6-naphthyridin-2(1H)-one, m.p.238°-240° C. This compound was the same as the compound of Example E-7a,e.g., a mixed melting point showed no depression and the infrared andnuclear magnetic resonance spectral data for the compounds wererespectively the same.

E-8 5-Ethyl-1,6-naphthyridin-2(1H)-one--A mixture containing 8.2 g of6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone, 3.9 g offormamidine acetate and 100 ml of dimethylformamide was refluxed in anoil bath for 5 hours and then evaporated to dryness on a rotaryevaporator. The residue was recrystallized from ethanol and dried at90°-95° C. to yield 5.5 g of product, m.p. 182°-184° C. This product wasrecrystallized from isopropyl alcohol and dried at 90°-95° C. to produce4.4 g of 5-ethyl-1,6-naphthyridin-2(1H)-one, m.p. 186°-188° C.

Acid-addition salts and cationic salts of this compound can be preparedfollowing the procedure described in Example E-7a.

E-9. 1,5-Dimethyl-1,6-naphthyridin-2(1H)-one--A mixture containing 4.5 gof 5-methyl-1,6-naphthyridin-2(1H)-one, 15 ml of dimethylformamide and 4ml of dimethylformamide dimethyl acetal was stirred at room temperatureovernight, then heated on a steam bath for 7 hours and then evaporatedto dryness on a rotary evaporator. The solid residue was recrystallizedfrom isopropyl alcohol and dried at 90°-95° C. to yield 3.5 g of1,5-dimethyl-1,6-naphthyridin-2(1H)-one, m.p. 203°-205° C.

E-10 1,2-Dihydro-5,6-dimethyl-2-oxo-1,6-naphthyridinium4-Methylbenzenesulohonate--A mixture containing 8 g of5-methyl-1,6-naphthyridin-2(1H)-one, 12 g of methyl4-methylbenzenesulphonate and 100 ml of dimethylformamide was heated ona steam bath for 5 hours and then concentrated on a rotary evaporator.The solid residue was refluxed with 100 ml of methanol, the productcollected and dried at 90°-95° C. to produce 13.6 g of1,2-dihydro-5,6-dimethyl-2-oxo-1,6-naphthyridinium4-methylbenzensulphonate, m.p. 253°-255° C.

Following the procedure described in Example 7b but using in place of5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone a molar equivalentquantity of the appropriate 5-(RCO)-6-[2 (R₁ R₂N)ethenyl]-2(1H)-pyridinone and in place of formamidine acetate a molarequivalent quantity of ammonium acetate, it is contemplated that thecompounds of Examples E-11 through E-14 can be obtained.

E-11. 5-n-Propyl-1,6-naphthyridin-2(1H)-one, m.p. 201°-203° C. as itsmethanesulfonate, using5-(n-butanoyl)-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone.

E-12. 5-Methyl-1,6-naphthyridin-2(1H)-one, using5-acetyl-6-(2-diethylaminoethenyl)-2(1H)-pyridinone.

E-13. 5-n-Butyl-1,6-naphthyridin-2(1H)-one, using6-(2-dimethylaminoethenyl)-5-(n-pentanoyl)-2(1H)-pyridinone.

E-14. 5-Isopropyl-1,6-naphthyridin-2(1H)-one, using6-(2-dimethylaminoethenyl)-5-(3-methyl-n-propanoyl)-2(1H)-pyridinone.

Prior art 1,6-naphthyridin-2(1H)-one was prepared as follows: A mixturecontaining 16 g of 5-methyl-1,6-naphthyridin-2(1H)-one, 200 ml of aceticacid and 22 g of selenium oxide was refluxed for twenty-four hours andfiltered while hot. The insoluble material was washed with 300 ml of hotmethanol and the combined filtrate (including washings) was concentratedto dryness on a rotary evaporator. The remaining yellow residue wasdissolved in 400 ml of boiling distilled water, the mixture treated withdecolorizing charcoal and filtered, and the filtrate concentrated on arotary evaporator to yield a residue. The latter was refluxed with 200ml of ethanol and the mixture cooled. The pale yellow solid wascollected, washed with ethanol and dried at 90° C. to yield 7.4 g. of1,6-naphthyridin-2(1H)-one, m.p. 295°-297° C.

The usefulness of the compounds of formula I where Q is hydrogen,hydroxy, amino, cyano or carbamyl and 1,6-naphthyridin-2(1H)-one ascardiotonic agents is demonstrated by their effectiveness in standardpharmacological test procedures, for example, in causing a significantincrease in contractile force of the isolated cat or guinea pig atriaand papillary muscle and/or in causing a significant increase in cardiaccontractile force in the anesthetized dog with lower or minimal changesin heart rate and blood pressure. Detailed descriptions of these testprocedures appear in U.S. Pat. No. 4,072,746, issued Feb. 7, 1980.

When tested by said isolated cat or guinea pig atria and papillarymuscle procedure, the compounds of formula I where Q is hydrogen,hydroxy, amino, cyano or carbamyl at doses of 0.3, 1, 10, 30 and/or 100μg/ml., were found to cause significant increases, that is, greater than25% (cat) or 30% (g.pig) in papillary muscle force and significantincreases, that is, greater than 25% (cat) or 30% (g.pig) in rightatrial force, while causing a lower percentage increase (about one-halfor less than the percentage increase in right atrial force or papillarymuscle force) in right atrial rate. Because of the lower control activetensions of guinea pig tissues, the percent change from control valuesof both rate and force responses is elevated slightly, i.e., 5%. Thus,whereas cardiotonic activity is ascertained with a papillary muscleforce or right atrial force increase of 26% and greater in the cat test,corresponding activity in the guinea pig test is designated with apapillary muscle force or right atrial force increase of 31% or greater.For example, when tested by said guinea pig atria and papillary muscleprocedure, the following illustrative compounds were found to causerespective papillary muscle force and right atrial force increases asfollows: Example E-4, 40% and 47% at 3 μg/ml, 135% and 77% at 10 μg/ml,and 119% and 168% at 30 μg/ml; Example E-5, 85% and 54% at 10 μg/ml, and68% and 45% at 30 μg/ml; Example E-9, 102% and 199% at 100 μg/ml;Example E-10, 94% and 90% at 100 μg/ml; Example E-11, 55% and 91% at 1.0μg/ml and 111 % and 161% at 10.0 μg/ml; Example E-7a, 63% and 47% at 1μg/ml, 87% and 88% at 3 μg/ml; and 102% and 116% at 10 μg/ml; and,Example E-8, 87% and 67% at 0.3 μg/ml, 130% and 107% at 1 μg/ml and 136%and 129% at 3 μg/ml. When tested by said corresponding cat atria andpapillary muscle procedure, the following illustrative compounds werefound to cause respective papillary muscle force and right atrial forceincreases as follows: Example E-1, 96% and 53% at 10 μg/ml; and, ExampleE-2, 83% and 18% at 100 μg/ml.

Prior art 1,6-naphthyridin-2(1H)-one when tested by said guinea pigatria and papillary muscle procedure was found to cause respectivepapillary muscle force and right atrial force increases as follows: 42%and 25% at 10 μg/ml, 65% and 50% at 30 μg/ml and 91% and 87% at 100μg/ml. In contrast, as shown above, applicants'5-methyl-1,6-naphthyridin-2(1H)-one was found to cause respectivepapillary muscle force and right atrial force increases as follows: 63%and 47% at 1.0 μg/ml, 87% and 88% at 3.0 μg/ml, and 102% and 116% at10.0 μg/ml, that is, at only one-tenth the respective doses foundnecessary for said prior art 1,6-naphthyridin-2(1H)-one. When tested bysaid anesthetized dog procedure, applicants'5-methyl-1,6-naphthyridin-2(1H)-one was found to be about twice asactive as 1,6-naphthyridin-2(1H)-one at only one-tenth the dose.

When tested by said anesthetized dog procedure, the compounds of formulaI where Q is hydrogen, hydroxy, amino, cyano or carbamyl at doses of0.01, 0.03, 0.10, 0.30, 1.0 and/or 3.0 mg/kg administered intravenouslywere found to cause significant increases, that is, 25% or greater, incardiac contractile force or cardiac contractility with lower changes inheart rate and blood pressure. For example, when tested at one or moreof said dose levels by this procedure, the compounds of Examples E-1,E-4, E-5, E-7a, E-8, E-9, E-10 and E-11 were found to cause increases ofabout 32% to 200% in contractile force and lower changes in heart rateand blood pressure.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier and, as the activecomponent thereof, the compound of formula I where Q is hydrogen,hydroxy, amino, cyano or carbamyl. The invention also includes withinits scope the method for increasing cardiac contractility in a patientrequiring such treatment which comprises administering to such patient acardiotonically effective amount of the compound of formula I where Q ishydrogen, hydroxy, amino, cyano or carbamyl or1,6-naphthyridin-2(1H)-one. In clinical practice said compound willnormally be administered orally or parenterally in a wide variety ofdosage forms

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions mayalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc, and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water andliquid paraffin. Besides inert diluents such compositions may alsocontain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic ester such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilizing, preserving,wetting, emulsifying and dispersing agents

They can be sterilized, for example by filtration through abacterial-retaining filter, by incorporation of sterilizing agents inthe compositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active component in the said composition and methodfor increasing cardiac contractility can be varied to that a suitabledosage is obtained. The dosage administered to a particular patient isvariable depending upon the clinician's judgement using as the criteria:the route of administration, the duration of treatment, the size andcondition of the patient, the potency of the active component and thepatient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing his best judgement on the patient's behalf.

We claim:
 1. 1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-one having theformula ##STR4## or a pharmaceutically acceptable acid-addition orcationic salt thereof, where R is lower-alkyl, R' is hydrogen or methyl,R" is hydrogen or lower-alkyl, and Q is hydrogen, hydroxy or amino.
 2. Acompound according to claim 1 where R is methyl, ethyl or propyl, R' andR" are each hydrogen, and Q is hydrogen, hydroxy or amino. 3.5-Methyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 4.5-Ethyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 5.5-n-Propyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 6.3-Hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 7.3-Amino-5-methyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 8.1,5-Dimethyl-1,6-naphthyridin-2(1H)-one according to claim
 1. 9. Acardiotonic composition for increasing cardiac contractility whichcomprises a pharmaceutically acceptable carrier and, as the activecomponent thereof, a cardiotonically effective amount of the1-R"-3-Q-4-R'-R-1,6-naphthyridin-2(1H)-one of claim 1 orpharmaceutically acceptable acid-addition or cationic salt thereof,where R, R' and R" have the meanings given in claim 1, and Q ishydrogen, hydroxy or amino.
 10. A cardiotonic composition according toclaim 9 where in the active component R is methyl, ethyl or propyl,R'and R" are each hydrogen, and Q is hydrogen, hydroxy or amino.
 11. Acardiotonic composition according to claim 9 where the active componentis 5-methyl-1,6-naphthyridin-2(1H)-one.
 12. A cardiotonic compositionaccording to claim 9 where the active component is5-ethyl-1,6-naphthridin-2(1H)-one.
 13. A cardiotonic compositionaccording to claim 9 where the active component is5-n-propyl-1,6-naphthyridin-2(1H)-one.
 14. A method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient a cardiotonically effective amount of the1-R"-3-Q-4-R'-5-R-1,6-naphthyridin-2(1H)-one of claim 1 or1,6-naphthyridin-2(1H)-one or pharmaceutically acceptable acid-additionor cationic salt thereof, where R, R' and R" have the meanings given inclaim 1 and Q is hydrogen, hydroxy or amino.
 15. A method according toclaim 14 where in the active component R is methyl, ethyl or propyl, R'and R" are each hydrogen, and Q is hydrogen, hydroxy or amino.
 16. Amethod according to claim 14 where the active component is5-methyl-1,6-naphthyridin-2(1H)-one.
 17. A method according to claim 14where the active component is 5-ethyl-1,6-naphthyridin-2(1H)-one.
 18. Amethod according to claim 14 where the active component is5-n-propyl-1,6-naphthyridin-2(1H) one. 19.1,2-Dihydro-5,6-dimethyl-2-oxo-1,6-naphthyridinium4-methylbenzenesulfonate.